Brain microglia become activated and upregulate pro-(and anti-) inflammatory signaling in response to neuronal cell damage, injury and invasion of the CNS by microbes. Osteopontin (OPN, secreted phosphoprotein-1, SPP1), is highly upregulated in Alzheimer?s disease (AD) and several other neurodegenerative disorders and piqued our interest in pursuing additional mechanistic studies into its function in the central nervous system. An understanding of the molecular mechanisms that underlie the development of the neuropathologic changes and inflammatory processes over time in these disorders remains incompletely understood, and are critical barriers to the development of urgently needed treatments for the growing population of those affected. Interestingly, a ?neurodegenerative? microglia gene signature that includes OPN/SPP1 was described for AD. We have been using a mouse model of viral infection as the initial disruptor of brain homeostasis to investigate the role of OPN/SPP1 in neuronal injury and inflammation. We found using translocator protein (TSPO, [11C-DPA-713]) PET-neuroimaging of buffer controls versus HIV-infected humanized mice with knockdown of OPN/SPP1 expression or not, that OPN/SPP1 is a master regulator of microglial inflammatory signaling. A second well characterized marker of activated microglia, Iba-1 was also found by immunohistochemistry (IHC) to be significantly increased. With the prior link of OPN/SPP1 to the neurodegenerative microglia phenotype, we tested whether expression of other members of the reported signature were altered in our mice. To our surprise, we found that antisera against mouse ApoE revealed abundant staining of neurons and glial cells, as well as plaque-like structures and numerous ApoE- associated microparticles in the brains of HIV-infected mice expressing OPN/SPP1, but absent or low in those of HIV-infected OPN-, or OPN+ or OPN- buffer injected mice. We are very excited and believe that our model system, presents for the first time the opportunity to begin to dissect the molecular mechanisms of microglial activation and to test novel hypotheses centered on a regulatory role for OPN/SPP1 in ApoE- associated lipoprotein aggregation and neuropathogenesis. With the central role of microglia in AD, this line of investigation will fill critical gaps in knowledge needed for the advancement of therapeutic approaches aimed at microglia dysfunction.